(1) Field of the Invention
The present invention generally relates to compounds having pharmacological activity which are useful as pharmaceutical agents and, more particularly, as analgesic agents for the treatment of pain, to pharmaceutical compositions containing one or more of these compounds, and to methods of treatment employing these compounds. More particularly, the present invention concerns substituted dibenzoxazepine compounds, pharmaceutical compositions containing one or more of these compounds in combination with a pharmaceutically-acceptable carrier, and medical methods of treating pain employing these compounds.
Analgesic compounds are agents which alleviate pain without causing a loss of consciousness and, thus, which are useful for treating pain and, often, for reducing inflammation.
The major classes of analgesic compounds include narcotic analgesics, or opiates, compounds which alleviate pain and induce sleep, and analgesic-antipyretic compounds, compounds which alleviate pain and reduce fever, such as salicylates.
Although the efficacy of opiates in relieving pain is well established, the associated addiction liability of opiates is a distinct disadvantage of these compounds.
While salicylate and salicylate-like agents (nonsteroidal antiinflammatory agents or NSAIDS) are also efficacious in relieving pain, they often exhibit undesirable side effects, such as gastrointestinal irritation, as with aspirin, allergic response, as with aspirin, and/or liver toxicity with extended use, as with acetaminophen.
The compounds of the present invention are neither opiates nor salicylates, and represent another class of compounds which are useful as analgesic agents.
(2) Description of the Related Art
U.S. Pat. No. 3,357,998 discloses amides of dihydrodibenzo[b,f][1,41oxazepine-10-carboxylic acids.
U.S. Pat. No. 3,644,346 discloses semicarbazones of dibenzoxazepine-N-carboxylic acid hydrazides.
U.S. Pat. No. 4,221,715 discloses dibenz[b,f][1,4]oxazepine-11-yl pyridinium salts and derivatives thereof.
U.S. Pat. No. 4,434,171 discloses 5,6-dihydro-5-(4-piperidinyl)-11H-dibenz[b,e]azepines.
U.S. Pat. No. 4,360,525 discloses 10-(4-piperidinyl)-10,11-dihydro-dibenz[b,f][1,4]oxazepines, -dibenzo[b,f][1,4]thiazepines and -5H-dibenzo[b,e][1,4]diazepines.
U.S. Pat. No. 4,379,150 discloses dibenz[b,f][1,4]-oxazepine derivatives which are substituted at the 10-position with the group --A--NR.sub.4 R.sub.5, wherein A is a lower alkylene group, and wherein R.sub.4 and R.sub.5 may be taken together with a nitrogen atom to form a heterocyclic ring.
European Patent Application Publication Nos. 0 534 667 A1 and 0 480 641 A1 disclose tricyclic heterocycles which are stated to counteract mild to moderate pain by virtue of their anti-hyperalgesic properties.
German Patent Application Publication No. 1,170,322 discloses dibenz[b,f][1,4]oxazepine-11(10H)-ones which are substituted at the 10-position with the group --A--CO--NR.sub.5 R.sub.6, wherein A may be a saturated aliphatic hydrocarbon group, and wherein R.sub.5 and R.sub.6 may represent cycloalkyl.
CH 648-309-A discloses N-methyl-piperidinyl dibenzazepine derivatives for use as neuroleptics, antidepressants and hypnotics.
K. Nagarajan et al., "Synthesis of 10,11-Dihydrodibenz-[b,f][1,4]oxazepine Derivatives as Potential Anticonvulsants & Psychotropic Agents," Indian Journal of Chemistry, 24B, 840-844 (1985), disclose the synthesis of acyl, carbamoyl and thiocarbamoyl derivatives of 10,11-dihydrodibenz[b,f][1,4]oxazepine, most of which have either a nitro or an amino group at position-2, as analogues of carbamazepine, and the evaluation of these derivatives as anticonvulsants associated with neuroleptic activity.
W. E. Coyne et al., "Anticonvulsant Semicarbazides," J. Med. Chem., 11(6), 1158-1160 (1968), disclose the investigation of the structure-activity relationship of the anticonvulsant activity of a series of semicarbazides which was synthesized from various tricyclic amines (see Table I, Page 1160).
Margaret E. Greig et al., "Effects of a Group of Dibenzodiazepines on Fatal Systemic Anaphylaxis in Mice, Rats and Guinea Pigs," J. Med. Chem., 14(2), 153-153 (1970), discloses a series of dibenzodiazepines which was tested for protection against fatal systemic anaphalaxis in mice, rats and guinea pigs.
Each of the documents described hereinabove discloses compounds which are structurally different from the compounds of the present invention. Thus, the compounds of the present invention are structurally distinct from that which has been described in the art.
Compounds within the present invention have been found to exhibit activity as prostaglandin E.sub.2 antagonists, and have been found to have few side effects, and no potential for the release of hydrazine, which is toxic.